A major goal of immunologic research in HIV/AIDS is to determine whether "natural" protective immunity exists against infection and disease progression, and if so, to elucidate the mechanisms of such protection. This information might provide insight into the design of effective vaccines and immune-based therapeutic strategies against HIV/AIDS. This laboratory was the first to establish that individuals within several different cohorts HIV-exposed people exhibited potent cellular immunity against HIV. In keeping with my interest in this area, our current efforts have been to develop models in which in vitro stimulation of blood leukocytes from uninfected and HIV-infected individuals with different antigens such as influenza virus (FLU) and allogeneic leukocytes (ALLO) stimulated the production of soluble factors that inhibit HIV infection in vitro. We found that both of the above stimuli induced the production of multiple factors that blocked the HIV infection cycle prior to reverse transcription. FLU stimulation induced mainly IFN-a production, and inhibited not only HIV-1 virus replication, but also HTLV-1 (associated with T cell leukemia) and HHV-8 (associated with Kaposi's sarcoma) infection. ALLO stimulation inhibited HIV-1 but not the other viruses, and did not induce IFN-a production. However, the generation of potent ALLO-stimulated HIV inhibitory activity was associated with expression of the HLA-A2 gene. This finding is consistent with epidemiologic reports indicating that vertical transmission of HIV was reduced by 10-fold if the HIV-infected mothers were maximally different from their newborns at HLA and by an additional 9-fold if the infants expressed HLA-A2. These parallel findings raise the possibility that the soluble factors that we are studying contribute to protection against transmission of HIV.